Sustained release aminopyridine composition

a technology of aminopyridine and composition, which is applied in the direction of drug compositions, biocide, heterocyclic compound active ingredients, etc., can solve the problems of affecting the effect of treatment, and promoting the transmission of spinal cord nerves, so as to achieve enhanced dosage stability, chemical and physical stability, and superior resistance to moisture absorption

Active Publication Date: 2005-12-15
ACORDA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Benefits of technology

[0013] The dispersion of 4-aminopyridine throughout the matrix imparts chemical and physical stability to the composition while providing a sustained-release profile. This enhanced dosage stability is most notably observed in compositions and dosage forms of the present invention having low concentrations of 4-aminopyridine, and stability is achieved while maintaining the desired controlled-release profile. Specifically, the compressed tablet formulation of the present invention exhibits superior resistance to moisture absorption by ambient humidity and maintains a uniform distribution of the 4-aminopyridine throughout the tablet while providing a release profile of 4-aminopyridine that permits establishment of a therapeutically effective concentration of the potassium channel blocker with once daily or twice daily dosing of the formulation. Preferably the therapeutically effective concentration released by the formulation extends over at least 6 hours, preferably at least 8 hours, and more preferably to at least 12 hours. In addition, the homogeneity of the dosage form renders it amenable to formation by simple and inexpensive manufacturing processes as compared with the multi-layered structure of prior sustained-release dosage formulations.
[0014] The compositions of the present i

Problems solved by technology

Treatment alternatives for promoting transmission along injured nerves of the spinal cord have thus far met with limited success.
The condition of MS involves demyelination of nerve fibers resulting in short-circuiting of nerve impulses and thus a slowing or blocking of transmission along the nerve fibers, with associated disabling symptoms.
Treatment alternatives for promoting transmission along affected nerves have thus far been limited.
The emotional state, behavior, cognitive function and thought proc

Method used

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  • Sustained release aminopyridine composition
  • Sustained release aminopyridine composition
  • Sustained release aminopyridine composition

Examples

Experimental program
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Effect test

example 1

[0095] This example illustrates preparation of compositions of the present invention and their release of an aminopyridine. Tablets in accordance with the present invention having dosages of 5 mg, 7.5 mg and 12.5 mg respectively were manufactured at 5 Kg scale. Materials were used in the amounts shown in Table 1.

TABLE 1% w / w% w / w% w / wMilled 4-AP1.251.8753.125(#50 mesh)Methocel K100LV606060Avicel PH10138.1537.52536.275Magnesium stearate0.20.20.2Aerosil 2000.40.40.4Equipment TabletHorn Noak equipped with 13 × 8 mm oval toolingPresspress speed 42,000 tablets / hrTablet Weight Range386-404388-410388-406(mg)(96.5-101.0%)(97.0-102.5%)(97.0-101.5%)Tablet Hardness Range200-262179-292150-268(N)Tablet Potency -97.199.1100.2mg / tab. (% LC)Mean CU (mg / tab.) / 5.0 mg / 1.0%7.4 mg / 0.7%12.4 mg / 1.1%% CVCU Discrete Samples5.0 mg / 1.2%7.5 mg / 1.8%12.3 / 1.1%(mg / tab.) / % CVDissolution (% / hr)Mean(SD)Mean(SD)Mean(SD) 128.91.129.21.825.91.1 242.71.842.11.640.22.5 352.81.453.01.049.82.1 461.42.261.81.560.12.4 675.7...

example 2

[0096] This example illustrates that the pharmacokinetic profile of fampridine in compositions of the present invention is altered by administration in a sustained release tablet matrix compared to immediate release and controlled release formulations.

[0097] There is a delay in absorption manifested by a lower peak concentration, without any effect on the extent of absorption. When given as a single 12.5 mg dose, the peak concentration is approximately two-thirds lower as compared to peak values following administration of the IR formulation; the time to reach peak plasma levels was delayed by about 2 hours. FIG. 1 is a graph of mean plasma profiles associated with the administration to a patient in both fasted and fed states of a tablet form of 4-AP (fampridine) in accordance with the present invention compared with the mean plasma profile associated with the administration of an immediate release (IR) formulation. As with the IR formulation, food delayed the absorption of Famprid...

example 3

[0099] This example details the plasma concentration of different dosage tablets of a aminopyridine in compositions of the present invention administered to patients with spinal cord injury. Pharmacokinetic results are presented for the subset of 11 patients who completed all dose levels. Maximal plasma concentrations and AUC values increased with increasing dose, with a mean Cmax of 152.0 ng / mL at the highest dose of 120 mg / day. The time of the peak and the plasma elimination half-lives were independent of dose. Mean Tmax ranged from 2.2 hours to 3.0 hours. The T1 / 2 of fampridine ranged from 5.7 to 6.9 hours. There were no apparent differences between males and females. Data from this study are summarized in Table 3.

TABLE 3Pharmacokinetic Parameter Values (Mean ± SD) Following Multiple OralDoses of Fampridine-SR to 11 Patients with SCI.Fampridine-SR DosageCMAXTMAXAUC(0-12)T1 / 2(mg b.i.d.)(ng / mL)(hours)(ng hr / mL)(hours)2563.4 ± 11.92.2 ± 0.9475.8 ± 65.5 6.4 ± 1.43083.2 ± 20.52.4 ± ...

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Abstract

A pharmaceutical composition which comprises a therapeutically effective amount of a aminopyridine dispersed in a release matrix, including, for example, a composition that can be formulated into a stable, sustained-release oral dosage formulation, such as a tablet which provides, upon administration to a patient, a therapeutically effective plasma level of the aminopyridine for a period of at least 12 hours, preferably 24 hours or more and the use of the composition to treat various neurological diseases.

Description

CROSS REFERENCES [0001] This application relates to U.S. Provisional Application Ser. No. 60 / 528,760, filed Dec. 11, 2003, U.S. Provisional Application No. 60 / 560,894 filed Apr. 9, 2004, U.S. Provisional Application No. 60 / 528,592 filed Dec. 11, 2003, 60 / 528,593 filed Dec. 11, 2003, and PCT / US2004 / 008101 filed on Mar. 17, 2004, all of which are incorporated herein by reference in their entirety.BACKGROUND [0002] This invention relates to a sustained release oral dosage form of an aminopyridine pharmaceutical composition that can be used to treat individuals affected with neurological disorders wherein said pharmaceutical composition maximizes the therapeutic effect, while minimizing adverse side effects. [0003] The sustained release oral dosage form of the present invention may be utilized to treat neurological disorders such as spinal cord injuries, multiple sclerosis, Alzheimer's disease, and ALS. Spinal cord injuries are one of the leading causes of disability in young adults res...

Claims

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Application Information

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IPC IPC(8): A61K9/20A61K9/22A61K31/44
CPCA61K9/2054A61K31/44A61K9/2077A61K47/44A61K47/14A61K47/38A61K31/4409A61P19/00A61P25/00A61P25/28A61P43/00A61K47/12A61K9/20
Inventor CUNNINGHAM, SEANBLIGHT, ANDREW R.
Owner ACORDA THERAPEUTICS INC
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